Intraperitoneal administration of m-chlorophenylpiperazine (m-CPP) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) to rats produced significant increases in plasma concentrations of prolactin, adrenocorticotropic hormone (ACTH) and corticosterone. We observed the development of tolerance in ACTH responses after a single injection of m-CPP. However, there was no cross-tolerance to DOI when chronic (13 days) m-CPP-treated animals were challenged with DOI. On the other hand, daily injections of DOI for six days were required before tolerance developed to DOI's effect on ACTH. Furthermore, cross-tolerance was observed when DOI-treated (2.5 mg/kg/dayx6) animals were challenged with m-CPP (2.5 mg/kg) on day 7. In contrast, daily administration of m-CPP and DOI for 13 days did not produce tolerance to their stimulating effects on corticosterone and prolactin secretion. These findings suggest that DOI and m-CPP induced ACTH secretion in rats is mediated by separate mechanisms, most likely by selective stimulation of serotonin (5-HT2A and 5-HT2C) receptors, respectively. In another study, pretreatment with various NMDA receptor antagonists such as 5,7- dichlorokynurenic acid, 3-amino-1-hydroxy-2-pyrrolidone, dizocilpine and ifenprodil injected 30 minutes before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 hr later with the same dose of m-CPP. These findings suggest that tolerance to this postsynaptic 5-HT2C receptor-mediated response is initiated through stimulation of the NMDA receptor complex. In a separate series of experiments in Fawn-Hooded rats, long-term (16 days) treatment with the tricyclic antidepressant, imipramine, the 5-HT uptake inhibiting antidepressant, fluoxetine and the noradrenergic uptake inhibiting antidepressant, desipramine accentuated clonidine's effect on growth hormone levels. These findings suggest enhancement of 5-HT2C receptor-mediated function following long-term treatment with uptake inhibiting antidepressants in a genetic animal model of depression.